https://www.google.com/patents/EP3122330A1?

cl=en

Usually, the first coating represents 0% to 40 % per weight with respect to the total weight of the
granule. Particularly, the first coating represents 0% to 30 % per weight with respect to the total weight
of the granule. The first coating represents preferably 0% to 25 % per weight with respect to the total
weight of the granule.

https://patents.google.com/patent/US20060083786A1/en

In yet another embodiment of the present invention, the core of the composition can contain various
pharmaceutical additives in combination with the API requiring taste-masking. Examples of such
additives include, but are not limited to, antioxidants, buffering agents, sweetening agents, binders,
diluents, fillers, glidants, lubricating agents, disintegrants, wetting agents and the like and mixtures
thereof. Each of the foregoing additives, when used, is used at a functionally effective amount to impart
the desired properties to the pharmaceutical formulations herein.

[0058]

In one embodiment of the present invention, the content of the core in the composition of the present
invention generally varies from about 70 percent by weight to about 95 percent by weight, based on the
total weight of the composition. Preferably, the core varies from about 80 percent by weight to about
90 percent by weight of the total coated composition. The shape and size of the core is not limited and
may range from truly spherical to irregular and non-uniform. Preferably, the core is finished to granules
having a size ranging from about 150 to about 500 microns.

[0059]

The more preferred oral solid preparation is a tablet. A tablet may be prepared by direct compression,
wet granulation, or molding, of the substantially crystalline form of levocetirizine dihydrochloride with a
carrier and other excipients in a manner known to those skilled in the art. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as
powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or
dispersing agent. Molded tablets may be made on a suitable machine, a mixture of the powdered
compound moistened with an inert liquid diluent, are suitable in the case of oral solid dosage forms
(e.g., powders, capsules, and tablets). The levocetirizine or pharmaceutically acceptable salt thereof may
be formulated into a typical disintegrating tablet in any release form, e.g., controlled release, extended
release, or immediate release dosage forms.
[0060]

Preferably, each tablet contains from about 2.5 mg to about 10 mg of levocetirizine or pharmaceutically
acceptable salt thereof, and each cachet or capsule contains from about 2.5 mg to about 10 mg of
levocetirizine or pharmaceutically acceptable salt thereof. Most preferably, the tablet contains about 5
mg of levocetirizine or pharmaceutically acceptable salt thereof for oral administration. The prophylactic
or therapeutic dose of levocetirizine or pharmaceutically acceptable salt thereof can vary widely
depending upon a variety of factors including, for example, the body weight, general health, sex, diet,
time and route of administration, rates of absorption and excretion, combination with other drugs, the
severity of the particular condition being treated, etc. The dose and perhaps the dose frequency will also
vary according to the age, body weight and response of the individual patient. In general, the total daily
dose range for levocetirizine or pharmaceutically acceptable salt thereof is from about 2.5 mg to about
10 mg. Preferably, a daily dose range should be about 5 mg to about 10 mg in single or divided doses.
Most preferably, the dose range is about 5 mg per day. It is known that children and elderly patients, as
well as those with impaired renal or hepatic function, should receive low doses, at least initially.

[0061]

The pharmaceutical compositions of the present invention can contain one or more pharmaceutically
acceptable excipients in accordance with known and established practice. The amount of the additional
pharmaceutically acceptable excipients generally varies from about 10% to about 90% by weight, based
on the total weight of the total composition. The pharmaceutically acceptable excipients include, but
are not limited to, fillers, glidants, lubricants, bulking agents, disintegrating agents and the like that are
typically used in the art for oral solid dosage forms.

[0062]

Suitable fillers for use herein may be, for example, inert fillers, either water soluble or water insoluble
and selected from those typically used in the pharmaceutical art for oral solid dosage forms. Examples
include, but are not limited to, lactose (monohydrate/dihydrate), starch dried, aspartame, crospovidone,
mannitol (Perlitol SD 200), sorbitol, sodium chloride and the like and mixtures thereof. The amount of
filler varies widely and will ordinarily range from about 1% to about 90% by weight, based on the total
weight of the composition.

[0063]

Suitable glidants for use herein can be any glidant typically used in the pharmaceutical art for oral solid
dosage forms. Examples include, but are not limited to, colloidal silicon dioxide, talc and the like and
mixtures thereof. The amount of glidant varies widely and will ordinarily range from about 0.1% to
about 5.0% by weight, based on the total weight of the composition.

[0064]

Suitable lubricants for use herein can be any lubricant typically used in the pharmaceutical art for oral
solid dosage forms. Example include, but are not limited to, stearate salts such as calcium stearate,
magnesium stearate, and zinc stearate, stearic acid, talc, hydrogenated vegetable oil, vegetable oil
derivatives, silica, silicones, high molecular weight polyalkylene glycols and saturated fatty acids and the
like and mixtures thereof. The amount of lubricant varies widely and will ordinarily range from about
0.1% to about 5.0% by weight, based on the total weight of the composition.

[0065]

Examples of a bulking agent include lactose monohydrate, cornstarch (dried), mannitol and the like and
mixtures thereof. The amount of bulking agent varies widely and will ordinarily range from about 4% to
about 15% by weight, based on the total weight of the composition.

[0066]

A suitable disintegrating agent includes crospovidone which is available as a white, free flowing
compressible powder. Crospovidone is a cross-linked N-vinyl-2-pyrrolidone homopolymer. It is
completely insoluble in water, acids, alkalis and all organic solvents. Crospovidone may also help in
enhancing the dissolution of pharmaceutically active substance and in turn enhances the bioavailability
for the same.

[0067]

Another excipient that may be used in the present invention is submicroscopic fumed silica with a
particle size of about 15 nm. It is a light, loose, bluish-white colored, odorless, tasteless, gritless
amorphous powder. As colloidal silicon dioxide has a small particle size and a large surface area give it
desirable flow characteristics, and so used as a glidant to improve the flow ability of the dried granules.

[0068]

The pharmaceutical composition of the present invention can further contain agents that generate
effervescence e.g. anhydrous citric acid and sodium bicarbonate (dried), which in contact with water
evolves carbon dioxide and produces effervescence.

[0069]

Formulations for oral use of the pharmaceutical compositions of the present invention can be provided
as effervescent mouth dissolving tablets wherein the pharmacologically active ingredients are mixed
with the inert excipients to form the effervescent mouth dissolving tablet pharmaceutical composition
of the present invention according to procedures known in the art.

[0070]

In another embodiment of the present invention, oral dosage forms of the pharmaceutical compositions
herein can be obtained by (a) slugging the active pharmaceutical ingredient along with diluents; (b)
deslugging the slugs obtained in step (b); (c) lubricating the product of step (b) with a lubricant; and (d)
tableting the mixture.
[0071]

The following example is provided to enable one skilled in the art to practice the invention and is merely
illustrative of the invention. The examples should not be read as limiting the scope of the claims.

Relative Humidity during manufacturing and packaging of the tablet should be maintained between
about 25 to about 30% and room temperature between about 21 to about 25° C.

[0000]

Preparation of the Tablet

[0000]

Step I: Manufacturing of Levocetirizine Dihydrochloride Granules

[0074]

Levocetirizine Dihydrochloride and aluminium magnesium silicate (Veegum HV) were sifted using a
mechanical sifter through a 40# sieve and mixed thoroughly in an octagonal blender for two to three
minutes. 3 min. Lactose (directly compressible) was then added to the mixture and mixed. Starch dried
and lake Ponceau 4 R were sifted through 40# sieve and collected in a separate polybag lined container.
Aspartame, crospovidone, anhydrous citric acid, sodium chloride and colloidal silicon dioxide were sifted
through 40# sieve and collect in a separate polybag and magnesium stearate was added.

[0075]

Levocetirizine dihydrochloride, aluminium magnesium silicate (Veegum HV), lactose (directly

compressible), starch (dried), Lake Ponceau 4R, aspartame, crospovidone, anhydrous citric acid, sodium
chloride, colloidal silicon dioxide were mixed for 15 minutes an magnesium stearate was added to the
mixture and mixed for an additional 3 minutes. The blend was unloaded in polybag lined drums.

[0000]

Step II: Slugging

[0076]

The blend from step I was slugged using a 16 mm Round biplane puncher with a 16/27 station rotary
compression machine. The slugs were then sifted through an Oscillating Granulator using an 8#, a 12#
and a 18# sieve or multimill the slugs through 6 mm SS screen (750 rpm), 4 mm SS screen (750, 1500
rpm), a 2 mm SS screen (1500 rpm) and then passed through a 18# sieve with about 3 kg fine powder
being kept for mixing with the lubricants.

[0077]
Sodium bicarbonate was sifted using a mechanical sifter through a 60# sieve. Next, the sifted sodium
bicarbonate was dried in a Tray Dryer at 100° C. for 1 hour and unloaded in a dehumidified area. The
weight was then measured and any loss on drying was compensated by adding an additional quantity of
sodium bicarbonate (previously dried).

[0000]

Step III: Lubrication

[0078]

Starch and Lake Ponceau 4R were sifted using mechanical sifter through a 0# sieve and collected in a
polybag lined container. Sodium bicarbonate, mannitol (Perlitol SD 200), crospovidone , firmenich
powder tuttifruity (colorcon) and firmenich powder flavor mint (colorcon), colloidal silicon dioxide were
sifted through a 40# sieve and collected in a polybag. Next, sodium bicarbonate, mannitol (Perlitol SD
200), crospovidone, firmenich powder tuttifruity (colorcon), firmenich powder flavor mint (colorcon),
and colloidal silicon dioxide were added to the polybag to form a lubrication premix.

[0079]

The granules from step II were then loaded in an octagonal blender and mixed for 5 minutes. Next, the
lubrication premix was added in the blender and mixed for 15 minutes. Magnesium stearate was then
added and mixed for an additional 3 minutes. The lubricated granules were then put in polybag lined
drums.

[0000]

Step IV: Compression

[0080]

The lubricated granules from step III were compressed into tablets using 8.4 mm flat-faced beveled edge
punches with breakline on upper punch and lower punch plain at 16/27 station rotary compression
machine observing the specifications. The tablets were compressed with an average compression
weight of 215 grams and a hardness of 2-4 kg/cm2.